Scheme 1 SCHEMATIC REPRESENTATION OF THE CASCADE OF THE COMMON SPORADIC FORMS OF ALZHEIMER'S DISEASE
(see Ref.4 for the extended bibliography for the scheme)
Neuronal cholesterol dynamics misregulation causes the key Alzheimer's disease (AD) feature of learning and memory failure as a result of the impairment of neuronal function, neurotransmission and synaptic plasticity through the mechanisms precise molecular nature which remains to be identified.
Cholesterol-mediated change in neurochemistry of amyloid beta, tau phosphorylation, neuronal cytoskeleton rearrangements and the modulation of physiological equilibrium of oxidative stress reactions could provide physiological transitory mechanisms aiming to compensate impaired brain cholesterol dynamics and neurotransmission and synaptic plasticity.
The break in neuronal cholesterol homeostasis may require very long (i.e. chronic) onset time frame due to the physiologically slow turnover of the central nervous system (CNS) cholesterol. Such condition may be genetically set (right top) and be assisted environmentally by the long term dietary habits. While during the past 30 years the concept of healthy food has become synonymous with avoiding dietary cholesterol, the question of how this avoidance and its compensation affects brain cholesterol chemistry, learning and memory remained non-addressed for many years. Several basic reports, however, documented that brain cholesterol is a delicate substance very sensitive to many influences, ranging from lipid preparation diets and chemical delivery systems for drugs and food additives (cyclodextrins, for example) to learning process itself. It is thus possible that antifat lifestyle “soft science” doctrine contributed to the increase of dementia and Alzheimer's prevalence in industrialised countries during 1970s and 1980s.
The indicated physiological compensatory changes may slowly invert when neuronal cholesterol dynamics is recovering slow to the initial physiological level. Such reversibility was proved experimentally (see Ref. 4) and certified by nature as an important mechanism of the CNS plasticity, as exampled by high expression of PHF-phosphorylated tau during an ontogenic period of cholesterol-demanding intense neuritic outgrowth. General compensatory nature of amyloid and tau neurochemistry modulation was proposed previously and is illustrated by its change observed under related to cholesterol (but different from AD) cardiovascular and Niemann-Pick type C pathologies, as well as in normal cases and during aging.
When neuronal cholesterol dynamics is not recovering compensatory mechanisms fail yielding (yet possible reversible) the development of conventional Alzheimer's disease hallmarks (right). These hallmarks, however, are not causative for the sporadic AD, and thus unlikely represent the proper target for the efficient AD therapy, as supported by the cognitive decline and dementia in AD patients without detectable lesions. Of these disease markers demonized amyloid beta pathology is the key enemy for the amyloid cascade hypothesis.
Plaque amyloid may itself impair (dotted arrows) synaptic plasticity and learning, neural networks, protein phosphorylation and oxidative stress status. Therefore it may have separate pathogenetic significance for the familial forms of AD, caused by the mutations in amyloid precursor protein and presenilins genes.
Similarly, oxidative stress independently disrupts synaptic plasticity and thus may have separate pathogenic value for the Down syndrome (characterized by upregulation of the reactions of oxidative stress due to the possible overexpression of the enzyme Cu/Zn-superoxide dismutase (SOD1), a chromosome 21 gene product) and for the pre-plaque stages of AD. The hallmarks trigger third order events of microglia activation, astrocytosis, cytokine/acute-phase protein release and cell death (not shown). This may convert physiological compensation into the pathological final and lock the cascade and the disease irreversibility.